Colorectal cancer and colitis-associated cancer, a subtype of colorectal cancer associated with inflammatory bowel disease (IBD), are major health risks and leading causes of death. Colon carcinogenesis is generally regarded as being composed of multiple stages of sequential mutations of some oncogenes and tumor suppress. The most common initiating event of colorectal carcinogenesis is mutation of the adenomatous polyposis coli (APC) gene, which leads to activation of the Wnt/&#946;-catenin pathway. Identification of molecular events that regulate tumorigenesis after APC loss is important for understanding the mechanism of colon carcinogenesis and therapeutic development. Wnt signaling via &#946;-catenin is critically important in regulating normal crypt cell homeostasis and is dysregulated in colon carcinogenesis. Almost all colorectal cancers exhibit mutation of either APC or &#946;-catenin, which leads to the blockade of phosphorylation by GSK-3, resulting in &#946;-catenin stabilization and enhanced Wnt/&#946;-catenin signaling. During the course of tumorigenesis, additional mutations (such as KRAS and TP53) are usually acquired. It has long been recognized that chronic IBD increases the risk of colorectal cancer. The transcription factor NF-&#954;B has also been shown to be a key factor linking inflammation and immunity to cancer development and progression. A recent study showed that NF-&#954;B could enhance Wnt signaling, leading to the dedifferentiation of epithelial non-stem cells into tumor-initiating cells. However, clearly defining the regulatory mechanism of Wnt signaling and its role in colon carcinogenesis continues to present a challenge. Olfactomedin 4 (OLFM4) is an evolutionarily conserved glycoprotein that belongs to an olfactomedin family. It was first cloned in human hematopoietic myeloid cells and is also abundantly expressed in intestinal crypts. It affects a diverse set of cellular processes, including proliferation, differentiation, apoptosis, adhesion, and innate immunity against bacterial infections. OLFM4 transcription is regulated by PU.1, NF-&#954;B, Notch, and retinoic acids. Its expression is also regulated epigenetically through promoter methylation. OLFM4 expression is upregulated in human IBD, which comprises ulcerative colitis and Crohns disease. OLFM4 interacts with NOD1 and NOD2, which are intracellular sensors for bacterial infection that have been found to be associated with Crohns disease. A recent study has demonstrated that OLFM4 is a robust marker for intestinal Lgr5-positive stem cells. OLFM4 tends to be overexpressed in early-stage colon cancer, but reduced or lost in advanced stages of the disease .These observations suggest that OLFM4 may play a role in the transition from colon adenoma to dysplastic tumors. Here we explored this possibility and found that Olfm4 deletion in ApcMin/+ mice leads to upregulation of Wnt/&#946;-catenin signaling genes and carcinoma formation in the distal colon. We also observed that Olfm4-deficient mice exhibited robust intestinal crypt hyperplasia and severe inflammation in an azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colitis-associated cancer model. In addition, we showed that OLFM4 is a both a target gene and an inhibitor of the Wnt/&#946;-catenin pathway.